Chronic inflammation in gastrointestinal epithelia is characterized by alterations in the cytokine milieu and often predisposes to the development of neoplasia. Primary sclerosing cholangitis, a chronic inflammatory condition affecting the biliary system, is associated with cytokine alterations and the development of cholangiocarcinoma. Dysregulation of apoptosis has recently been implicated as an important contributor to carcinogenesis. We have recently shown that the pro- inflammatory cytokine IL-6 alters the susceptibility of biliary epithelial cells to undergo apoptosis by downregulating Bax, a member of the Bcl-2 family and a dominant tumor suppressor and pro-apoptotic gene. Thus, our HYPOTHESIS is that dysregulation of apoptosis by cytokines is an important mechanism of malignant transformation of biliary epithelia. The SPECIFIC AIMS for this proposal are: 1) To test the hypothesis that pro-inflammatory cytokines such as IL-1, IL-6 and TNFalpha regulate apoptosis by altering the expression or activity of members of the Bcl-2 family of apoptosis regulators; 2) to test the hypothesis that IL-6 alters expression of Bax by a ligand mediated activation of specific signaling pathways resulting in altered gene transcription; and 3) to test the hypothesis that dysregulation of apoptosis by cytokines enhances malignant transformation in biliary epithelial cells due to genotoxic injury. These studies will help to determine the role of cytokines in injury and transformation of biliary epithelia and expand our understanding of the mechanisms mediating malignant transformation in inflammatory states. This information has the promise of ultimately contributing to the development of specific therapies for the cholangiopathies as well as interventions to prevent neoplasia.